Xanthine Oxidase Inhibitor Step Therapy with Quantity

Limit Criteria Program Summary This step therapy applies to Commercial and Health Insurance Marketplace formularies

only.

Quantity limits apply to all formularies.

This program is implemented with grandfathering.

OBJECTIVE The intent of the step therapy criteria for Xanthine Oxidase Inhibitor is to encourage the use of cost-effective generic allopurinol 300 mg before brand agents and to accommodate for use of brand agents when allopurinol cannot be used due to documented intolerance, FDA labeled contraindication, or hypersensitivity. This step therapy program will require use of the 300 mg allopurinol tablet because clinical literature shows that most patients with moderate gout require 400 mg to 600 mg/day to lower serum uric acid below 6.0 mg/dL. The program allows continuation of therapy when there is documentation that the patient is receiving the requested agent. Requests for brand agents will be reviewed when patient-specific documentation has been provided.

TARGET DRUG Uloric (febuxostat)

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Xanthine Oxidase Inhibitor will be approved when ANY ONE of the following is met: 1. The patient’s medication history includes use of allopurinol 300 mg in the past 90 days OR 2. There is documentation that the patient is currently using the requested agent OR 3. The prescriber states the patient is currently using the requested agent AND is at risk if therapy is changed OR 4. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to allopurinol 300 mg

Length of approval: 12 months

NOTE: If Quantity Limit program also applies, please refer to Quantity Limit documents.

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© Copyright Prime Therapeutics LLC. 04/2016 All Rights Reserved Drug Indication1 Dosage Uloric®  Febuxostat is indicated  Febuxostat starting (febuxostat) for the chronic dose is 40 mg once management of daily. tablets hyperuricemia in  For patients who do not 40 mg & 80 mg patients with gout. achieve serum uric acid  Uloric is not (sUA) < 6 mg/dL after recommended for the two weeks of treatment, treatment of 80 mg is recommended asymptomatic once daily. hyperuricemia.  For those who have achieved sUA < 6 mg/dL, 40 mg once daily is the recommended dosage.

CLINICAL RATIONALE Guidelines The goals of gout treatment are threefold: treating acute inflammation, preventing flares, and lowering serum urate levels. The goal of therapy with urate-lowering drugs is to reduce the serum urate level to <6.0 mg/dL, noting that some patients may need lowering to <5.0 mg/dL to durably improve signs and symptoms of gout.2,10 Monitoring of serum urate is recommended every 2-5 weeks during urate lowering therapy titration, and every 6 months once serum urate target is achieved.2

The Evidence, Expertise, Exchange Initiative (3E) (2014) provided multinational evidence-based recommendations for management of gout, integrating systematic literature review and expert opinion of a broad panel of rheumatologists. There was strong consensus that allopurinol constitutes first line urate lowering therapy after consideration of its safety, efficacy and cost. Uricosurics and low to medium doses of febuxostat are considered alternatives in the presence of intolerance or nonresponsiveness to allopurinol.14

The American College of Rheumatology (ACR) 2012 Guidelines for the Management of Gout2,3 recommend diet and lifestyle measures for the majority of patients with gout. In addition, these pharmacologic therapies are recommended:2  Xanthine oxidase inhibitors allopurinol and febuxostat are first line agents for pharmacologic urate lowering therapy. The ACR did not preferentially recommend either xanthine oxidase inhibitor, but they did note there was a lack of published safety data for febuxostat in the setting of severe chronic kidney disease (CKD).  Probenecid was recommended as an alternative to a xanthine oxidase inhibitor in the setting of contraindication or intolerance to ≥ 1 xanthine oxidase inhibitor. Also, probenecid is not recommended for monotherapy in those with a creatinine clearance of < 50 mL/minute.  For refractory gout, febuxostat can be substituted for allopurinol in the event of drug intolerance or adverse events.  Effective therapeutic options include addition of a uricosuric agent such as probenecid to a xanthine oxidase inhibitor for refractory gout.  Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, conventional and appropriately dosed urate lowering therapy. Pegloticase is not recommended as first line urate lowering therapy for any case scenarios.

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© Copyright Prime Therapeutics LLC. 04/2016 All Rights Reserved Allopurinol is the first-line therapy for most patients and has been the mainstay of prophylactic treatment for gout and conditions associated with hyperuricemia for over 40 years. 2,4,10 Allopurinol is effective in most patients with hyperuricemia if a sufficient dose is taken, but achieving normal serum urate levels may be difficult in patients with impaired renal function or in transplant recipients.9 Febuxostat is considered an alternative to allopurinol.13

Clinical data supporting the dose escalation of allopurinol from 300 mg daily to 300 mg twice daily measured the percentage of patients who achieved a serum uric acid level of ≤ 5 mg/dL. Dose escalation increased the response rate from 26% (for 300 mg daily) to 78% (for 300 mg twice daily).4 Two large observational studies (one in heart failure and one in hyperuricemic patients) have shown that allopurinol is associated with reduced total mortality.5,6 Two small randomized controlled trials showed allopurinol reduced cardiovascular events markedly in both studies.7,8

The ACR states that the recommended initial dose of allopurinol should not exceed 100 mg/day and should be less for patients with moderate to severe chronic kidney disease (50mg/day).2 The rationale for starting the initial dose at ≤ 100 mg/day is that “a low dose could reduce early gout flares after urate lowering therapy initiation, and as a component risk management with respect to the potential for severe hypersensitivity reaction to allopurinol.”2

Febuxostat Efficacy Two of the pivotal trials submitted to the FDA for approval of febuxostat (FACT, APEX) studied the efficacy of different doses of febuxostat versus placebo and allopurinol in the treatment of hyperuricemia in patients with gout.10,11  Patients had been randomized within these two clinical trials to receive placebo or once-daily febuxostat at a dose of 80 mg, 120 mg, or 240 mg, or once-daily allopurinol at 100 mg, 200 mg, or 300 mg. For gout flare prophylaxis during the first 8 weeks of these trials, patients received naproxen 250 mg twice daily or colchicines 0.6 mg once daily. Primary endpoints were the proportion of patients with sAU levels less than 6.0 mg/dL both at their last three visits and at their final visit.  None of the patients in the placebo group satisfied the specified endpoints for sUA <6.0 mg/dL.  In the allopurinol 200 mg/d treatment group, for the last three patient visits and at the final patient visit, respectively, these endpoints were satisfied for a significantly greater proportion over the placebo group, at 46% and 66% (P ≤.01 for both).10  Febuxostat treatment satisfied the two endpoints by significantly greater proportions of patients than seen with placebo and with allopurinol at all doses (febuxostat 80 mg, 72%, 94%; febuxostat 120 mg, 78%, 89%; febuxostat 240 mg, 77%, 100%; P ≤ 0.01 in all cases)

CONFIRMS, the largest, pivotal, phase 3 clinical trial, showed that febuxostat 80 mg was superior to febuxostat 40 mg and allopurinol 300/200 mg at achieving the main study outcome of serum uric acid less than 6.0 mg/dL at the final visit (67%, 47%, and 42%, respectively; P < .001 for both comparisons).12 It should be noted that clinical trials comparing febuxostat with allopurinol included doses of allopurinol up to 300 mg/day maximum. Evidence has demonstrated that 50% of patients with hyperuricemia and gout require higher doses of allopurinol to achieve the required serum uric acid <6 mg/dL.12

Febuxostat Safety Febuxostat is contraindicated in patients being treated with azathioprine, mercaptopurine or theophylline.10 The most common adverse event leading to discontinuation from therapy with febuxostat was liver function abnormalities in 1.8% of the patients treated with the 40 mg dose and 1.2% of those treated with the 80 mg dose.10 Unlike allopurinol, febuxostat can be

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REFERENCES 1. Uloric Prescribing Information. Takeda Pharmaceuticals America, Inc, Deerfield, Il. November 2013. 2. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for the management of gout part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care & Res. 2012;64(10):1431-1446. 3. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for the management of gout part 2: Therapy and antiinflammatory prophylaxis of gouty arthritis. Arthritis Care & Res. 2012;64(10):1447-1461. 4. Sarawate CA, Brewer KK, Yang W, et al. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc. 2006; 81:925–934 5. Luk AJ, Levin GP, Moore EE, Allopurinol and mortality in hyperuricaemic patients Rheumatology. 2009;48:804-806. 6. Thanassoulis G, Brophy JM, Hugues R, et al. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med 2010;170(15):1358-1364. 7. Rentoukas E, Tsarouhas K, Tsitsimpikou C, et al. The prognostic impact of allopurinol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Int J Cardiol. 2010;145:257–258. 8. Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388– 1393. 9. Gaffo AL, Saag KG. Management of hyperuricemia and gout in CKD. Am J Kid Dis. 2008;52(5):994-1009. 10. Becker MA, Schumacher Jr HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450- 2461. 11. Becker MA, Schumacher Jr HR, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase; a twenty eight day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005;52(3):916-923. 12. Becker MA, Schumacher HR, Espinoza LR, WEllsAF, MacDonaldP, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12:R63, 13. Medical Letter Treatment Guidelines. Drugs for gout. 2014;56(1438):21-23. 14. Sivera F, Andres M, Carmona L, et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann Rheum Dis 2014;73:328-335.

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